C. Dopamine Agonists
These drugs directly activate D2 receptors and can be used as monotherapy in Parkinsonism. Ergot derived dopamine agonists include bromocriptine and pergolide. These drugs are short acting and can cause digital vasosopasm (leading to gangrene) and erythromelalgia. These drugs can also result in pleural, peritoneal and cardiac fibrosis. Ergot alkaloids require slow upward titration of dose. Long term use of pergolide is associated with cardiac valvular defects.
Newer non-ergot dopamine agonists; pramipexole and ropinirole do not have these limitations (these are long acting and do not cause gangrene). All four drugs can cause confusion and hallucinations. In developed countries, these are now the first choice drugs for Parkinsonism (preferred over levo-dopa). Ropinirole has also been approved for restless leg syndrome. Pramipexole is excreted mainly by kidney whereas ropinirole is metabolized by liver. Rare but important adverse effect of these drugs is excessive day time sleepiness. Recently, dopamine agonists have been associated with impulse-control disorders including pathological gambling, hypersexuality, etc. Rotigotine is a dopamine agonist that can be administered through a transdermal patch but was discontinued due to crystal formation on the patches. Apomorphine can be given subcutaneously for temporary relief of off-periods. However, it cause troublesome nausea.
D. Drugs Increasing Dopamine Level at Synapse
Amantadine is an antiviral drug that is also useful in Parkinsonism. It increases synaptic dopamine level by increasing presynaptic release and decreasing its reuptake. It also possesses anticholinergic and antiglutaminergic (NMDA blocking) activity. Adverse effects of this drug include nausea, insomnia, ankle edema and livedo reticularis. It ameliorates dyskinesia associated with chronic levo-dopa therapy.
Drugs Inhibiting Brain Cholinergic Transmission
Central anticholinergic drugs like trihexiphenidyl (benzhexol), procyclidine, benztropine, orphenadrine and biperiden are the drugs of choice for drug induced Parkinsonism. Drugs that act by blocking D2 receptors in the brain (like antipsychotics, metoclopramide etc.) can cause Parkinsonism. In this condition, increasing dopamine level is not effective because the receptors on which it has to act (D2) are already occupied, therefore anticholinergics are preferred.
First generation antihistaminics with high antimuscarinic activity like promethazine and diphenhydramine can also be used for this indication.
Adverse effects of antimuscarinic drugs include urinary retention, blurred vision, dry mouth and constipation.
Some general points
- None of the above drugs alter the basic pathology of PD—the disease continues to progress.Drugs only provide symptomatic relief and give most patients an additional 3–6 years of happier and productive life. Considering that oxidative metabolism of DA generates free radicals which may rather hasten degeneration of nigrostriatal neurones, it has been argued that levodopa therapy might accelerate progression of PD. There is no proof yet for such a happening, and controlled prospective studies have not detected any difference in the progression of disease due to levodopa therapy. However, appearance of dyskinesias is related to dose and duration of levodopa therapy. Thus, it may be prudent to delay use of levodopa and begin with anticholinergics/amantadine/selegiline or newer direct DA agonists in early/mild/ younger patients.
- Initially, when disease is mild, only anticholinergics or selegiline may be sufficient. However, anticholinergics are often not tolerated by elderly patients, especially males. Monotherapy with newer DA agonists ropinirole or pramipexole is being increasingly employed for early cases, especially in younger patients, because of fewer motor complications. However, psychotic symptoms and sudden onset sleep has to be watched for. Selegiline may also be combined with levodopa during the deterioration phase of therapy to overcome ‘wearing off’ effect.
- Combination of levodopa with a decarboxylase inhibitor is the standard therapy, and has replaced levodopa alone. Slow and careful initiation over 2–3 months, increasing the dose as tolerance to early side effects develops and then maintenance at this level with frequent evaluation gives the best results. Full benefit lasts for about 2–3 years, then starts declining.
- Subsequently the duration of benefit from a levodopa dose progressively shortens—end of dose ‘wearing off’ effect is seen. Dyskinesias appear, mostly coinciding with the peak of levodopa action after each dose. Relief of parkinsonian symptoms gets linked to the production of dyskinesias. Still later (4–8 years) the ‘on-off’ phenomena and marked dyskinesias may become so prominent that the patient is as incapacitated with the drug as without it. However, withdrawal of levodopa or dopamine agonists, particularly when higher doses have been employed, may precipitate marked rigidity hampering even respiratory excursions, hyperthermia, mental deterioration and a state resembling the ‘neuroleptic malignant syndrome’.
- Combination of levodopa with decarboxylase inhibitor increases efficacy and reduces early but not late complications.
- Levodopa alone is now used only in those patients who develop intolerable dyskinesias with a levodopa-decarboxylase inhibitor combination.
- Amantadine may be used with levodopa for brief periods during exacerbations.
- The direct DA agonists, especially ropinirole/pramipexole, are commonly used to supplement levodopa in late cases to smoothen ‘on off’ phenomenon, to reduce levodopa dose and possibly limit dyskinesias.
- In advanced cases, the COMT inhibitor entacapone may be added to levodopa-carbidopa to prolong its action and subdue ‘on off’ fluctuation. It can be given to patients receiving selegiline or DA agonists as well.
- ‘Drug holiday’ (withdrawal of levodopa for 4–21 days) to reestablish striatal sensitivity to DA by increasing dopaminergic receptor population is no longer practiced.
(This is only for academic purpose and not a guideline for treatment, please visit your Doctor when needed. Do not use any drug without consultation with Doctor.)